Animal studies have shown that tricyclic antidepressants (TCAs) produce an initial blockade of norepinephrine and/or serotonin uptake and subsequent changes in one or more populations of pre- and post-synaptic neuronal receptors. However, there is controversy over which of these various effects is/are primarily responsible for the antidepressant action of the drugs. Thyroidal state also has been shown to affect the status of central neuronal receptors, though its effects, if any, on uptake mechanisms have not been studied extensively. The interdigitation of TCA and thyroidal effects is exemplified by clinical studies which have shown that the thyroid hormone L-triiodothronine (T3) accelerates the antidepressant action of TCAs in females and converts about two-thirds of TCA "failures" of both sexes to "successes". On the other hand, hypothyroidism prevents a favorable response to these drugs. Given these clinical observations, it is reasonable to assume that those TCA effects which are accelerated or enhanced by T3 or retarded or diminished by hypothyroidism are probably therapeutically important effects of these drugs. A general aim of the research in this proposal is to identify those effects. The focal point of the TCA-thyroidal interdigitation is the adrenergic systems; however, certain adrenergic changes (e.g. Beta-receptors) require intact serotonergic innervations. The interactive adrenergic and serotonergic effects of thyroidal state and TCAs have not been studied extensively. It is proposed here to determine how thyroidal state influences the effects of desmethylimipramine (DMI) and 3-chloroimipramine (CLI) on norepinephrine (NE) and serotonin (5-HT) uptake systems and post-synaptic adrenergic and serotonergic receptor populations. NE and 5-HT uptake and Beta-adrenergic and serotonergic receptors will be studied in cerebral cortex and other selected brain regions of hyperthyroid, hypothyroid and euthyroid rats and rats of these three thyroidal states which have been chronically treated with DMI or CLI. Information gained from this research may help to solve an important problem in contemporary psychopharmacology. With its solution, efforts to design more effective drugs can be focused, and our understanding of the pathogenesis of affective disorders will be enhanced.